Abstract 2301: Agonistic Autoantibodies Against the Endothelin 1 ETA - and α1-Adrenergic- Receptor in the Sera of Patients with Idiopathic Pulmonary Arterial Hypertension.
Background: Idiopathic pulmonary arterial hypertension (IPAH) is a progressive fatal disease of unknown cause. This disease is accompanied by an massive increase of pulmonary vascular resistance (remodelling and increase of vascular tonus) inducing right heart failure. It was shown that the synthesis of vasoconstrictors (endothelin 1, thromboxane A2, serotonine) is elevated in patients with IPAH.
Methods: We analyzed sera of patients with PH with regards to functional autoantibodies (AABs) against G-protein coupled receptors using spontaneously beating rat cardiomyocytes as bioassay. Moreover, we investigated the effect of the AAB on the translocation of the transcription factors NFκB and AP-1.
Results: The sera of patients with IPAH contain functional AABs against the α1-adrenergic (α1-AR) and the endothelin1 ETA receptor. We purified the AABs by affinity chromatography. AABs against the α1-AR exert a positive chronotropic effect. AABs against the ETA receptor induce like endothelin 1 a negative chronotropic effect. The agonistic effect of the AABs was dose-dependent and blocked by prazosine (α1-AR blocker) and BQ610 (ETA antagonist), respectively. Moreover, the agonistic effect of the AABs was neutralized by peptides corresponding to the second extracellular loop of both receptors. Therefore, the epitopes of the AABs are localized on the second extracellular loops of the receptors. The α1-AR AABs as well as the ETA-receptor AABs induce a permanent stimulation without desensitization of the receptor mediated signal cascade. The α1-adrenergic agonist phenylephrine and endothelin1 as ET receptor agonist cause a translocation of the transcription factor NFκB and AP-1 from the cytosol into the nucleus in cultured neonatal rat cardiomyocytes. The same translocation was observed using the AABs against the α1-AR and ETA receptor.
Conclusion: The agonist-like AABs against the α1-AR and the ETA receptor influence in vitro the signalling of cultured cells. Moreover, the AABs prevent the desensitization of the receptor mediated signal cascade normally seen by ongoing receptor stimulation. Therefore, we assumed that the functional AABs against the α1-AR and the ETA receptor may be involved in the pathogenesis of IPAH.